Method for producing 4,6-dichloropyrimidine with sulfur compounds and phosphorus compounds

ABSTRACT

The invention relates to a method for the preparation of 4,6-dichloropyrimidine by reacting 4-chloro-6-methoxypyrimidine with at least one sulphur-containing chlorinating agent selected from the group consisting of SCl 2 , SOCl 2 , and SO 2 Cl 2  in the presence of at least one phosphorus compound having the formula 
     
       
         R 3 P═Y n   (1), 
       
     
     in which 
     R represents C 1 -C 10 -alkyl or C 6 -C 10 -aryl, each of which may optionally be substituted by up to five identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, C 1 -C 4 -alkyl, and C 1 -C 4 -alkoxy, 
     Y represents oxygen or sulphur, and 
     n represents zero or 1.

The present invention relates to a method for the preparation of4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine.4,6-Dichloropyrimidine is a valuable intermediate for the preparation ofcrop protection agents.

A number of methods for preparing 4,6-dichloropyrimidine are knownstarting from 4,6-dihydroxypyrimidine.

It is also known (see Res. Discl. n 391, 690-691 (1996)) that4,6-dichloropyrimidine can be reacted by reacting4-chloro-6-methoxypyrimidine with a chlorinating agent of the formulaR₃PCl₂. The chlorinating agent can be employed as such or be prepared insitu from a compound of the formula R₃P═O and phosgene. It isadditionally described therein that 4-chloro-6-methoxypyrimidine doesnot react with phosphorus oxychloride. The disadvantage of this methodis that usually only very incomplete conversion can be achieved and thus4,6-dichloropyrimidine is obtainable only in low yields and low degreesof purity.

A method for the preparation of 4,6-dichloropyrimidine from4-chloro-6-methoxypyrimidine has now been found and is characterized inthat 4-chloro-6-methoxypyrimidine is reacted with at least onesulphur-containing chlorinating agent selected from the group of SCl₂,SOCl₂ and SO₂Cl₂ and in the presence of at least one phosphorus compoundof the formula

R₃P═Y_(n)  (1),

in which

R represents C₁-C₁₀-alkyl or C₆-C₁₀-aryl, each of which may optionallybe substituted by up to 5 identical or different substituents from thegroup of fluorine, chlorine, bromine, C₁-C₄-alkyl and C₁-C₄-alkoxy,

Y represents oxygen or sulphur

and

n represents zero or 1.

Preferred sulphur-containing chlorinating agents are SOCl₂ and SO₂Cl₂,and preferred phosphorus compounds are triphenylphosphine andtriphenylphosphine oxide.

Based on 1 mol of 4-chloro-6-methoxypyrimidine it is possible, forexample, to employ at least 1 mol of sulphur-containing chlorinatingagent. This amount is preferably 1 to 2 mol.

Based on 1 mol of sulphur-containing chlorinating agent it is possibleto employ, for example, 0.01 to 1 mol of phosphorus compounds of theformula (1). This amount is preferably 0.02 to 0.25, particularlypreferably 0.05 to 0.1, mol.

The method according to the invention is preferably carried out in thepresence of a solvent. Suitable examples are aromatic solvents such astoluene, xylenes, chlorobenzene, dichlorobenzenes, chlorotoluenes,benzonitrile and benzotrifluoride, nitrogen-containing solvents such asN-methylpyrrolidone, dimethylformamide, dimethylacetamide and cyclicureas and oxygen-containing solvents such as ethers, in particularhigher-boiling ethers and polyethers. It is also possible to employmixtures of solvents.

The method according to the invention can be carried out, for example,at temperatures in the range from 50 to 200° C. 75 to 175° C. arepreferred, especially 100 to 150° C.

The pressure is in principle not critical. Only if it is wished toemploy solvents which boil below the desired reaction temperature atatmospheric pressure is it indicated to operate under elevated pressureso that the solvent is present at least partly in liquid form.

On the assumption that, at the given temperature, no precursors,products and solvents escape from the reaction vessel, the pressure canbe, for example, in the range from 0.1 to 5 bar. The pressure ispreferably atmospheric, particularly preferably using a solvent whichboils under reflux at the required reaction temperature underatmospheric pressure.

The method of the invention can be carried out batchwise andcontinuously.

In a preferred embodiment of the method according to the invention,4-chloro-6-methoxypyrimidine, the phosphorus compound and a solvent aremixed, the mixture is heated to the reaction temperature, and then thesulphur-containing chlorinating agent is metered in, where appropriatein a plurality of portions.

The reaction mixture present after the reaction can be worked up, forexample, by distilling it through a column, where appropriate underreduced pressure.

It is possible with the method according to the invention to convert4-chloro-6-methoxypyrimidine into 4,6-dichloropyrimidine in a simplemanner. The conversion takes place virtually completely, in contrast tothe prior art. This makes it possible to prepare a product with a high4,6-dichloropyrimidine content in a simple manner. This is desirablebecause unreacted 4-chloro-6-methoxypyrimidine can be removed only withdifficulty by distillation.

EXAMPLES Example 1

29.0 g of 4-chloro-6-methoxypyrimidine and 5.6 g of triphenylphosphineoxide were introduced into 150 g of chlorobenzene and heated to 140° C.with stirring. 35.7 g of thionyl chloride were added dropwise to thissolution over the course of 1 hour. The mixture was then stirred at 140°C. After 6 hours, a further 11.9 g of thionyl chloride were addeddropwise, and then stirring was continued for 6 hours. This was followedby cooling to 25° C. A final weight of 304.1 g was obtained. HPLCanalysis showed a 4,6-dichloropyrimidine content of 9.34% (whichcorresponds to a yield of 95.3% of theory). The reaction mixturecontained only 0.1% 4-chloro-6-methoxypyrimidine (which corresponds to1.05% of the starting material).

Example 2

Example 1 was repeated, but 200 ml of a mixture of isomeric xylenes wereemployed in place of chlorobenzene, operating at 135° C. HPLC analysisshowed a 4,6-dichloropyrimidine yield of 93.6% and unreacted4-chloro-6-methoxypyrimidine in an amount of 2.6% of the startingmaterial.

Example 3

Example 1 was repeated but 49.2 g of a mixture of 3 moles of SOCl₂ and 1mole of SO₂Cl₂, in place of thionyl chloride were added dropwise overthe course of 1 hour and, after 6 hours, no further chlorinating agentwas added. HPLC analysis showed a 4,6-dichloropyrimidine yield of 89.3%of theory.

What is claimed is:
 1. A method for the preparation of 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine comprising reacting 4-chloro-6-methoxypyrimidine with at least one sulphur-containing chlorinating agent selected from the group consisting of SCl₂, SOCl₂, and SO₂Cl₂ in the presence of at least one phosphorus compound having the formula R₃P═Y_(n)  (1), in which R represents C₁-C₁₀-alkyl or C₆-C₁₀-aryl, each of which may optionally be substituted by up to five identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, C₁-C₄-alkyl, and C₁-C₄-alkoxy, Y represents oxygen or sulphur, and n represents zero or
 1. 2. A method according to claim 1 wherein the sulphur-containing chlorinating agent is SOCl₂ and/or SO₂Cl₂.
 3. A method according to claim 1 wherein the phosphorus compound is triphenylphosphine and/or triphenylphosphine oxide.
 4. A method according to claim 1 wherein at least 1 mol of the sulphur-containing chlorinating agent is used per 1 mol of 4-chloro-6-methoxypyrimidine.
 5. A method according to claim 1 wherein 0.01 to 1 mol of the phosphorus compound is used per 1 mol of the sulphur-containing chlorinating agent.
 6. A method according to claim 1 carried out in the presence of an aliphatic solvent, an aromatic solvent, a nitrile, a nitrogen-containing solvent, an ether, an oxygen-containing solvent, or a mixture thereof.
 7. A method according to claim 5 wherein the aromatic solvent is toluene, a xylene, chlorobenzene, a dichlorobenzene, a chlorotoluene, benzonitrile, benzotrifluoride, or a mixture thereof.
 8. A method according to claim 6 wherein the nitrogen-containing solvent is N-methylpyrrolidone, dimethylformamide, dimethylacetamide, or a cyclic urea or a mixture thereof.
 9. A method according to claim 6 wherein the oxygen-containing solvent is a polyether or a mixture of polyethers.
 10. A method according to claim 1 carried out at from 50 to 200° C. 